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Analyse des réseaux moléculaires impliqués dans le remodelage ventriculaire gauche post-infarctus du myocarde et dans l’insuffisance cardiaque

Abstract : Nowadays, cardiovascular diseases remain a main public health issue in developed countries.Following a myocardial infarction (MI), at least 30% of patients developed a left ventricularremodeling (LVR), that can lead to heart failure (HF) and to death. The aims of this project were tostudy the mechanisms involved in LVR post-MI and HF and to identify new biomarkers allowing theprediction of a deleterious evolution after MI and early death of HF patients by systems biology andstatistical approaches.First, we built a molecular network based on experimental data obtained in the plasma of post-MI patients of the REVE-2 study at 4 time-points (baseline, 1 month, 3 months and 1 year). An activemodule analysis, extracted at each time-point between patients with LVR and patients without LVR,and a betweenness centrality analysis allowed the selection of 6 molecules potentially involved inLVR : 2 transcription factors, EP300 and ESR1, and 4 microRNAs, miR-335-5p, miR-26b-5p, miR-375 and miR-17-5p. We showed that ESR1 mRNA was significantly increased at 2 months post-MI inthe LV a model of post-MI rats, miR-26b-5p was significantly decreased at 7 days post-MI and miR-335-5p had a trend to increase at 7 days post-MI.Secondly, we built a molecular network using the experimental data obtained by SOMAscanassay, in the plasma of patients diagnosed for systolic HF from the INCA study and followed during 3years. A topological and betweenness centrality analysis allowed the study of the mechanismsinvolved in HF. In parallel, a penalised regression analysis, performed in collaboration with the Bililleplatform, allowed the selection of 6 proteins (C3, MAPKAPK5, Cathepsin S, MMP-1, MMP-7 andFAM107B) that allowed the prediction of early death of HF patients. The quantification of C3, MMP-1 and MMP-7 by conventional assays (ELISA, Luminex) in a subset of the INCA population gaveconsisting results with the SOMAscan assay, but not for cathepsin S.
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Marie Cuvelliez. Analyse des réseaux moléculaires impliqués dans le remodelage ventriculaire gauche post-infarctus du myocarde et dans l’insuffisance cardiaque. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2019. Français. ⟨NNT : 2019LIL2S027⟩. ⟨tel-02614193⟩

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